From its start in the 1990's, high throughput screening (HTS) of chemical compound libraries has become an essential part of the drug discovery process with the successful generation of many lead molecules, clinical candidates and marketed pharmaceuticals (Curr. Opin. Chem. Biol. 2001, 5, 273-284; Curr. Opin. Chem. Biol. 2003, 7, 308-325; J. Biomol. Screen. 2006, 11, 864-869; Drug Disc. Today 2006, 11, 277-279; Nat. Rev. Drug Disc. 2011, 10, 188-195). Current collections of molecules for HTS, however, often are overpopulated by compounds related to known pharmaceutical agents, with a continuing need to expand chemical diversity and improve the content of screening collections (Curr. Opin. Chem. Biol. 2010, 14, 289-298; Drug Disc. Today 2013, 18, 298-304). Indeed, the diversity of molecular structures available in the library collections utilized for HTS has been identified as an area that needs to be dramatically improved (Curr. Opin. Chem. Biol. 2010, 14, 289-298; Biochem. Pharmacol. 2009, 78, 217-223; Curr. Med. Chem. 2009, 16, 4374-4381). Whereas the initial efforts at building screening libraries focused primarily on numbers of compounds, the focus has shifted to providing higher quality molecules (Fut. Med. Chem. 2014, 6, 497-502) that permit more complete sampling of “chemical space”. Fortunately, given the estimated vastness of this space (J. Chem. Info. Model. 2007, 47, 342-353), significant opportunity exists for finding and exploring new or underexplored compound classes for desirable biological activity.
As an additional consideration, HTS has traditionally varied considerably in success rate depending on the type of target being interrogated, with certain target classes identified as being particularly challenging, for example protein-protein interactions (PPI). To address such intractable targets, a wider range of compounds and chemotypes will need to be explored. This situation has been exacerbated as advances in genomics and proteomics have led to the identification and characterization of large numbers of new potential pharmacological targets (Nat. Rev. Drug Disc. 2002, 1, 727-730; Drug Disc. Today 2005, 10, 1607-1610; Nat. Biotechnol. 2006, 24, 805-815), many of which fall into these difficult classes.
Recently, macrocycles have been identified as an underexplored class of biologically relevant synthetic molecules that possess properties amenable to these more difficult targets (Nat. Rev. Drug Disc. 2008, 7, 608-624; J. Med. Chem. 2011, 54, 1961-2004; Fut. Med. Chem. 2012, 4, 1409-1438; Molecules 2013, 18, 6230-6268; J. Med. Chem. 2014, 57, 278-295; Curr. Pharm. Design 2016, 22, 4086-4093). Although such structures are widespread in natural products, considerable challenges of synthetic accessibility have to date limited their presence in screening collections.
The interest in macrocycles originates in part from their ability to bridge the gap between traditional small molecules and biomolecules such as proteins, nucleotides and antibodies. They are considered to fill an intermediate chemical space between these two broad classes, but possessing favorable features of each: the high potency and exceptional selectivity of biomolecules with the ease of manufacturing and formulation, favorable drug-like properties and attractive cost-of-goods of small molecules. Hence, macrocycles provide a novel approach to addressing targets on which existing screening collections have not proven effective.
Indeed, macrocycles display dense functionality in a rather compact structural framework, but still occupy a sufficiently large topological surface area to enable interaction at the disparate binding sites often present in PPI and other difficult targets. In addition, macrocycles possess defined conformations, which can preorganize interacting functionality into appropriate regions of three-dimensional space, thereby permitting high selectivity and potency to be achieved even in early stage hits. Interestingly, spatial or shape diversity in the design of libraries has been identified as an important factor for broad biological activity (J. Chem. Info. Comput. Sci. 2003, 43, 987-1003).
Although cyclic peptide libraries of both synthetic and biosynthetic origin have been prepared and studied in some depth (J. Comput. Aided. Mol. Des. 2002, 16, 415-430; Curr. Opin. Struct. Biol. 2013, 23, 571-580), libraries of macrocyclic non-peptidic or semi-peptidic structures remain more problematic to construct and their bioactivity only perfunctorily investigated (J. Med. Chem. 2011, 54, 1961-2004; Macrocycles in Drug Discovery, J. Levin, ed., RSC Publishing, 2015, pp 398-486, ISBN 978-1-84973-701-2).
Thiazoles, oxazoles and, to a lesser extent, imidazoles have been found to be common structural features of natural products, particularly those of marine origin (Marine Drugs. 2010, 8, 2755-2780; Nat. Prod. Rep. 2011, 28, 1143-1191; Nat. Prod. Rep. 2013, 30, 869-915). In fact, many such products contain multiple azole rings. In addition, compounds containing the thiazole ring have been found to have significant pharmacological and therapeutic impact (Curr. Top. Med. Chem. 2016, 16, 284-2862). Further, the imidazole ring, partly from its presence in the natural amino acid histidine, plays a vital role in many biological interactions due to its unique combination of basic and aromatic character (Curr. Med. Chem. 2006, 13, 1-23; Med. Chem. Res. 2011, 20, 1119-1140).
However, the incorporation of these heteroaromatic components into the ring backbone of synthetic macrocycles and libraries, as well as assessment of bioactivity for the resulting molecules, have not been widely explored (Org. Lett. 2003, 5, 4567-4570; J. Med. Chem. 2009, 52, 7014-7028; J. Org. Chem. 2010, 75, 7939-7941; Intl. Pat. Appl. Publ. WO 2012/062777; Tetrahedron 2012, 68, 1029-1051; Chem. Biodivers. 2012, 9, 2473-2484; J. Org. Chem. 2012, 77, 11079-11090; Chem. Rec. 2013, 13, 539-548; Proc. Natl. Acad. Sci. USA 2013, 110, E3753-E3760; ACS Comb. Sci. 2014, 16, 71-77).
Hence, the macrocyclic compounds and libraries of the disclosure, which include these heteroaryl moieties, provide distinct structural scaffolds from those previously known. In that manner, they satisfy a significant need in the art for novel compounds and libraries that are useful in the search for new therapeutic agents for the prevention or treatment of a wide variety of disease states.